Elevated levels of blood cholesterol have been associated with coronary artery disease which is one of the major causes of death in Western industrialized societies. The relationship between blood cholesterol and heart disease, although complicated, is now better understood. Cholesterol is an essential ingredient of mammalian cells, because it is needed for the cell membrane and some cells also require cholesterol to make certain hormones. Cholesterol is transported in body fluids by lipoproteins. The main lipoprotein implicated in heart disease is the low density lipoprotein (LDL). When LDL cholesterol levels in the blood are high, then the person is likely to suffer from atherosclerosis.
Two known compounds useful in reducing LDL cholesterol levels are Compactin and Mevinolin of the following formula: ##STR2## wherein R.sub.1 is H or methyl, respectively.
It has been found that these compounds possess the unusual property of lowering blood levels of cholesterol in animals, including man. It is thought that these compounds are reversible, competitive inhibitors of an important enzyme that is involved in cholesterol biosynthesis, which occurs mainly in the liver. When this enzyme in the synthesis is inhibited, cells manufacture more LDL receptors which thereby remove LDL cholesterol from the blood stream. The net result of administering either Compactin or Mevinolin to human beings is that the concentration in the blood of LDL cholesterol is reduced.
Difference in activity has been observed between Compactin wherein R is H, and Mevinolin, wherein R is methyl. Based on existing biological data, it appears that Mevinolin is several times more active in lowering LDL cholesterol levels as compared to Compactin. Although the fungal metabolites are useful in the treatment of elevated cholesterol blood levels, it is apparent that a synthetic route to these compounds would enable modifications in the structure of the compounds to be made so as to arrive at more active derivatives. Considerable thought has been given to the synthesis of these compounds and this work has been reviewed by T. Rosen and C. H. Heathcock, Tetrahedron 1986, 42:4909. The syntheses reviewed in this reference, however, lack stereocontrol and/or regiocontrol and/or are not sufficiently flexible to afford analogues without extensive redesign of the synthetic route. Hence it is difficult to produce by these known synthetic routes a range of optically pure analogues.